Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy

Abstract

The last two decades have seen a revival of interest in the entactogen 3,4-methylenedioxy-N-methylamphetamine (MDMA) as an adjunct to psychotherapy, particularly for the treatment of post-traumatic stress disorder. While clinical results are highly promising, and MDMA is expected to be approved as a treatment in the near future, it is currently the only compound in its class of action that is being actively investigated as a medicine. This lack of alternatives to MDMA may prove detrimental to patients who do not respond well to the particular mechanism of action of MDMA or whose treatment calls for a modification of MDMA’s effects. For instance, patients with existing cardiovascular conditions or with a prolonged history of stimulant drug use may not fit into the current model of MDMA-assisted psychotherapy, and could benefit from alternative drugs. This review examines the existing literature on a host of entactogenic drugs, which may prove to be useful alternatives in the future, paying particularly close attention to any neurotoxic risks, neuropharmacological mechanism of action and entactogenic commonalities with MDMA. The substances examined derive from the 1,3-benzodioxole, cathinone, benzofuran, aminoindane, indole and amphetamine classes. Several compounds from these classes are identified as potential alternatives to MDMA.

Hallucinogenic drugs and their potential for treating fear‐related disorders: Through the lens of fear extinction

“…It readily crosses the blood–brain barrier (Schenk & Newcombe, 2018) and increases synaptic levels of serotonin, and to a lesser extent dopamine and noradrenaline, by interacting with their transporters and preventing their reuptake (Feduccia & Mithoefer, 2018; Schenk & Newcombe, 2018). Additionally, MDMA can reverse the function of serotonin transporter, causing it to release serotonin into the synaptic cleft in exchange for transporting MDMA into the presynaptic neuron (Oeri, 2021). MDMA also promotes the release of oxytocin by stimulating hypothalamic 5‐HT 1A receptors (Thompson et al, 2007) and increases cortisol levels through the activation of hypothalamic–pituitary–adrenal axis (Parrott, 2009).…”

Ethnoracial health disparities and the ethnopsychopharmacology of psychedelic-assisted psychotherapies.

“…Once orally administered, MDMA exhibits effects, including positive mood, empathy, openness, and temporal and sensory-perceptual changes, within 30–60 min and maximally around 75–120 min (Multidisciplinary Association for Psychedelic Studies, 2019). Effects are primarily mediated by the efflux and accumulation of monoamine neurotransmitters in the synapses due to inhibition and reversal of 5-HT transporters (SERT), NE transporters (NET), and DA transporters (DAT), as well as inhibition of vesicular monoamine transporter 2 and agonism of a variety of other receptors, including 5-HT receptors (Kalant, 2001; Oeri, 2020). MDMA is metabolized via hepatic human cytochrome P450 CYP2D6-mediated O -demethylation, which converts MDMA to 4-hydroxy-3-methoxymethamphetamine (HMMA), as well as CYP1A2-mediated N -demethylation, which converts MDMA to 3,4-methylenedioxyamphetamine (MDA) (Hartman et al, 2014).…”

Molekularne podstawy działania wybranych substancji psychoaktywnych

“…4). Z tego też powodu ma również podobny do niej komórkowy mechanizm działania: konkuruje z monoaminami o miejsca wiązania, wywołuje odwrócony transport monoamin przez DAT, SERT i NET, zaburza upakowywanie monoamin w pęcherzyki wewnątrzkomórkowe oraz wpływa na zmniejszanie ilości transporterów wychwytu zwrotnego przez receptory TAAR1 [52]. MDMA jest silniejszym antagonistą SERT niż DAT i NET, a jej stosunek (DAT IC 50 ) -1 /(SERT IC 50 ) -1 jest bardzo niski i wynosi 0,1 [53,54].…”

“…Empatogenne właściwości MDMA powodują, że jest ona rozważana jako potencjalny lek w farmakoterapii niektórych zaburzeń psychicznych. W przypadku zespołu stresu pourazowego (PTSD), nawet jednorazowe zażycie MDMA długotrwale polepszało stan pacjentów [52]. MDMA obecnie jest już w trzeciej fazie badań klinicznych i z tego powodu wiele pracy poświęcono na zbadanie jej szkodliwości dla zdrowia [56].…”